心肌梗死后,巨噬细胞- trem2通过CXCL16-CXCR6轴抑制CD8+ T细胞的浸润,从而促进心脏修复。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI:10.7150/thno.118014
Linlin Zhang, Sheng Wang, Yu Ding, Tao Zheng, Jie Sheng, Yanshan Chen, Zhiyue Wang, Ximei Dai, Canbiao Wang, Long Ma, Jing Pan, Yunming Zhang, Longjiang Zhang
{"title":"心肌梗死后,巨噬细胞- trem2通过CXCL16-CXCR6轴抑制CD8+ T细胞的浸润,从而促进心脏修复。","authors":"Linlin Zhang, Sheng Wang, Yu Ding, Tao Zheng, Jie Sheng, Yanshan Chen, Zhiyue Wang, Ximei Dai, Canbiao Wang, Long Ma, Jing Pan, Yunming Zhang, Longjiang Zhang","doi":"10.7150/thno.118014","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> Infiltrated CD8<sup>+</sup> T cells following myocardial infarction (MI) are potential myocardial injury factors, triggering autoimmunity by binding to myocardial cell-specific proteins. It has been reported that autoimmunity after MI is restricted during the fibrosis period. Nevertheless, the relevant mechanisms of this process have scarcely been explored. Cell-cell communication analysis suggests that macrophages are the most promising group for restricting T cell activity. Unbiased single-cell sequencing data screening indicates that TREM2 is a leading gene significantly upregulated after MI. However, how TREM2 restricts the activity of CD8<sup>+</sup> T cells remains unknown. <b>Methods and Results:</b> The adoptive transfer of circulating CD8<sup>+</sup> T cells after MI proved their autoimmune attribute of attacking cardiomyocytes. CD8 antagonistic antibodies and the anti-autoimmune drug Ozanimod effectively inhibited the infiltration of CD8<sup>+</sup> T cells and significantly ameliorated the damage to cardiomyocytes after MI. In TREM2 KO mice, the infiltration of CD8<sup>+</sup> T cells in the myocardium was significantly increased without influencing the number of Treg cells. The results of cell-cell communication revealed that CXCL16-CXCR6 was the most predominant receptor-ligand pair between macrophages and CD8<sup>+</sup> T cells. The results of ELISA and Transwell indicated that TREM2 deficiency led to an increase in CXCL16 secretion, thereby enhancing the chemotaxis of CD8<sup>+</sup> T cells. The KEGG analysis and Western Blot results demonstrated that the deficiency of TREM2 augmented the activation of the PI3K-AKT signaling pathway, thereby resulting in an increase in CXCL16 secretion. Moreover, TREM2 deficiency also reduced VEGFC secretion and cardiac lymphangiogenesis, thereby leading to the impairment of immune cell drainage. Additionally, TREM2 deficiency reversed Ozanimod's effect on inhibiting CD8<sup>+</sup> T cell infiltration. The overexpression of TREM2 significantly decreased CD8<sup>+</sup> T cell infiltration and improved cardiac function. <b>Conclusions:</b> Macrophage TREM2 promotes cardiac repair by limiting the infiltration of CD8<sup>+</sup> T cells and facilitating lymphangiogenesis.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9580-9600"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486271/pdf/","citationCount":"0","resultStr":"{\"title\":\"Macrophage-TREM2 promotes cardiac repair by restricting the infiltration of CD8<sup>+</sup> T cells via CXCL16-CXCR6 axis after myocardial infarction.\",\"authors\":\"Linlin Zhang, Sheng Wang, Yu Ding, Tao Zheng, Jie Sheng, Yanshan Chen, Zhiyue Wang, Ximei Dai, Canbiao Wang, Long Ma, Jing Pan, Yunming Zhang, Longjiang Zhang\",\"doi\":\"10.7150/thno.118014\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background:</b> Infiltrated CD8<sup>+</sup> T cells following myocardial infarction (MI) are potential myocardial injury factors, triggering autoimmunity by binding to myocardial cell-specific proteins. It has been reported that autoimmunity after MI is restricted during the fibrosis period. Nevertheless, the relevant mechanisms of this process have scarcely been explored. Cell-cell communication analysis suggests that macrophages are the most promising group for restricting T cell activity. Unbiased single-cell sequencing data screening indicates that TREM2 is a leading gene significantly upregulated after MI. However, how TREM2 restricts the activity of CD8<sup>+</sup> T cells remains unknown. <b>Methods and Results:</b> The adoptive transfer of circulating CD8<sup>+</sup> T cells after MI proved their autoimmune attribute of attacking cardiomyocytes. CD8 antagonistic antibodies and the anti-autoimmune drug Ozanimod effectively inhibited the infiltration of CD8<sup>+</sup> T cells and significantly ameliorated the damage to cardiomyocytes after MI. In TREM2 KO mice, the infiltration of CD8<sup>+</sup> T cells in the myocardium was significantly increased without influencing the number of Treg cells. The results of cell-cell communication revealed that CXCL16-CXCR6 was the most predominant receptor-ligand pair between macrophages and CD8<sup>+</sup> T cells. The results of ELISA and Transwell indicated that TREM2 deficiency led to an increase in CXCL16 secretion, thereby enhancing the chemotaxis of CD8<sup>+</sup> T cells. The KEGG analysis and Western Blot results demonstrated that the deficiency of TREM2 augmented the activation of the PI3K-AKT signaling pathway, thereby resulting in an increase in CXCL16 secretion. Moreover, TREM2 deficiency also reduced VEGFC secretion and cardiac lymphangiogenesis, thereby leading to the impairment of immune cell drainage. Additionally, TREM2 deficiency reversed Ozanimod's effect on inhibiting CD8<sup>+</sup> T cell infiltration. The overexpression of TREM2 significantly decreased CD8<sup>+</sup> T cell infiltration and improved cardiac function. <b>Conclusions:</b> Macrophage TREM2 promotes cardiac repair by limiting the infiltration of CD8<sup>+</sup> T cells and facilitating lymphangiogenesis.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 18\",\"pages\":\"9580-9600\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486271/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.118014\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.118014","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

摘要

背景:心肌梗死(MI)后浸润的CD8+ T细胞是潜在的心肌损伤因子,通过与心肌细胞特异性蛋白结合触发自身免疫。有报道称心肌梗死后的自身免疫在纤维化期间受到限制。然而,这一进程的有关机制几乎没有得到探讨。细胞间通讯分析表明,巨噬细胞是最有希望限制T细胞活性的细胞群。无偏单细胞测序数据筛选表明,TREM2是心肌梗死后显著上调的先导基因。然而,TREM2如何限制CD8+ T细胞的活性尚不清楚。方法与结果:心肌梗死后循环CD8+ T细胞的过继转移证实了其攻击心肌细胞的自身免疫特性。CD8拮抗抗体和抗自身免疫药物Ozanimod能有效抑制心肌梗死后CD8+ T细胞的浸润,显著改善心肌细胞的损伤。TREM2 KO小鼠心肌中CD8+ T细胞的浸润明显增加,但不影响Treg细胞的数量。细胞间通讯结果显示,CXCL16-CXCR6是巨噬细胞和CD8+ T细胞之间最主要的受体-配体对。ELISA和Transwell结果表明,TREM2缺乏导致CXCL16分泌增加,从而增强CD8+ T细胞的趋化性。KEGG分析和Western Blot结果表明,TREM2缺失增强了PI3K-AKT信号通路的激活,从而导致CXCL16分泌增加。此外,TREM2缺乏还会减少VEGFC分泌和心脏淋巴管生成,从而导致免疫细胞引流功能受损。此外,TREM2缺乏逆转了Ozanimod抑制CD8+ T细胞浸润的作用。TREM2过表达可显著降低CD8+ T细胞浸润,改善心功能。结论:巨噬细胞TREM2通过限制CD8+ T细胞的浸润和促进淋巴管生成来促进心脏修复。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Macrophage-TREM2 promotes cardiac repair by restricting the infiltration of CD8+ T cells via CXCL16-CXCR6 axis after myocardial infarction.

Background: Infiltrated CD8+ T cells following myocardial infarction (MI) are potential myocardial injury factors, triggering autoimmunity by binding to myocardial cell-specific proteins. It has been reported that autoimmunity after MI is restricted during the fibrosis period. Nevertheless, the relevant mechanisms of this process have scarcely been explored. Cell-cell communication analysis suggests that macrophages are the most promising group for restricting T cell activity. Unbiased single-cell sequencing data screening indicates that TREM2 is a leading gene significantly upregulated after MI. However, how TREM2 restricts the activity of CD8+ T cells remains unknown. Methods and Results: The adoptive transfer of circulating CD8+ T cells after MI proved their autoimmune attribute of attacking cardiomyocytes. CD8 antagonistic antibodies and the anti-autoimmune drug Ozanimod effectively inhibited the infiltration of CD8+ T cells and significantly ameliorated the damage to cardiomyocytes after MI. In TREM2 KO mice, the infiltration of CD8+ T cells in the myocardium was significantly increased without influencing the number of Treg cells. The results of cell-cell communication revealed that CXCL16-CXCR6 was the most predominant receptor-ligand pair between macrophages and CD8+ T cells. The results of ELISA and Transwell indicated that TREM2 deficiency led to an increase in CXCL16 secretion, thereby enhancing the chemotaxis of CD8+ T cells. The KEGG analysis and Western Blot results demonstrated that the deficiency of TREM2 augmented the activation of the PI3K-AKT signaling pathway, thereby resulting in an increase in CXCL16 secretion. Moreover, TREM2 deficiency also reduced VEGFC secretion and cardiac lymphangiogenesis, thereby leading to the impairment of immune cell drainage. Additionally, TREM2 deficiency reversed Ozanimod's effect on inhibiting CD8+ T cell infiltration. The overexpression of TREM2 significantly decreased CD8+ T cell infiltration and improved cardiac function. Conclusions: Macrophage TREM2 promotes cardiac repair by limiting the infiltration of CD8+ T cells and facilitating lymphangiogenesis.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信